About Me

Tuesday, November 25, 2014

Moderator Jamie Metzl is joined by George Church, Professor of Genetics at Harvard Medical School, Columbia University bioethicist Robert Klitzman, New York Stem Cell Foundation Co-Founder and CEO Susan Solomon, and Princeton Professor of Molecular Biology and Public Policy Lee Silver to discuss the opportunities and challenges of human genetic engineering, among the most important issues of the coming millennia.

Sunday, November 23, 2014

NYBooks: ... In an interview about Citizenfour with the New Yorker reporter Jane Mayer, Snowden has said that his action seemed to him necessary because the American officials charged with the relevant oversight had abdicated their responsibility. He meant that President Obama, Attorney General Eric Holder, and the intelligence committees in the House of Representatives and the Senate had utterly failed to guard against extraordinary abuses of the public trust under the pretext of national security. Nor had they undertaken the proper work of setting limits to government spying on Americans consistent with the spirit of the First Amendment and the letter of the Fourth Amendment.

...Snowden is often called a “fanatic” or a “zealot,” a “techie” or a “geek,” by persons who want to cut him down to size. Usually these people have not listened to him beyond snippets lasting a few seconds on network news. But the chance to listen has been there for many months, in two short videos by Poitras on the website of The Guardian, and more recently in a full-length interview by the NBC anchorman Brian Williams. The temper and penetration of mind that one can discern in these interviews scarcely matches the description of fanatic or zealot, techie or geek.

An incidental strength of Citizenfour is that it will make such casual slanders harder to repeat. Nevertheless, they are likely to be repeated or anyway muttered in semiprivate by otherwise judicious persons who want to go on with their business head-down and not be bothered. It must be added that our past politics give no help in arriving at an apt description of Snowden and his action. The reason is that the world in which he worked is new. Perhaps one should think of him as a conscientious objector to the war on privacy — a respectful dissident who, having observed the repressive treatment endured by William Binney, Thomas Drake, and other recent whistle-blowers, does not recognize the constitutional right of the government to put him in prison indefinitely and bring him to trial for treason. ...

What seems most remarkable in that hotel room in Hong Kong is Snowden’s freedom from anxiety. He is fearful, yes ... He knows that he is at risk of being subjected to “rendition” or worse. But there is no theatrical exaggeration here, and no trace of self-absorption. He has made his commitment and that is that. ...

... [Snowden] realizes that if he keeps his identity a secret, the government will rally all its powers and those of the media to convert the treacherous and hidden leaker into the subject of the story. His intuition is that the best way to counter such a distraction will be to make the story personal right away, but to render the personal element dry and matter-of-fact. He will do this in the most unobtrusive and ordinary manner. He will simply admit that he is the person and spell out the few relevant facts about his life and work.

The undeclared subject of Citizenfour is integrity—the insistence by an individual that his life and the principle he lives by should be all of a piece.

Sisu is a Finnish term loosely translated into English as strength of will, determination, perseverance, and acting rationally in the face of adversity. However, the word is widely considered to lack a proper translation into any other language. Sisu contains a long-term element; it is not momentary courage, but the ability to sustain an action against the odds. Deciding on a course of action and then sticking to that decision against repeated failures is sisu. It is similar to equanimity, except the forbearance of sisu has a grimmer quality of stress management than the latter.

Friday, November 21, 2014

The recent SMPY paper below describes a group of mathematically gifted (top 1% ability) individuals who have been followed for 40 years. This is precisely the pool from which one would hope to draw STEM and technological leadership talent. There are 1037 men and 613 women in the study.

The figures show significant gender differences in life and career preferences, which affect choices and outcomes even after ability is controlled for. (Click for larger versions.) According to the results, SMPY men are more concerned with money, prestige, success, creating or inventing something with impact, etc. SMPY women prefer time and work flexibility, want to give back to the community, and are less comfortable advocating unpopular ideas. Some of these asymmetries are at the 0.5 SD level or greater. Here are three survey items with a ~ 0.4 SD or more asymmetry:

# Society should invest in my ideas because they are more important than those of other people.

# Discomforting others does not deter me from stating the facts.

# Receiving criticism from others does not inhibit me from expressing my thoughts.

I would guess that Silicon Valley entrepreneurs and leading technologists are typically about +2 SD on each of these items! One can directly estimate M/F ratios from these parameters ...

￼￼￼￼￼￼￼￼￼￼￼￼￼￼￼￼￼￼Two cohorts of intellectually talented 13-year-olds were identified in the 1970s (1972–1974 and 1976–1978) as being in the top 1% of mathematical reasoning ability (1,037 males, 613 females). About four decades later, data on their careers, accomplishments, psychological well-being, families, and life preferences and priorities were collected. Their accomplishments far exceeded base-rate expectations: Across the two cohorts, 4.1% had earned tenure at a major research university, 2.3% were top executives at “name brand” or Fortune 500 companies, and 2.4% were attorneys at major firms or organizations; participants had published 85 books and 7,572 refereed articles, secured 681 patents, and amassed $358 million in grants. For both males and females, mathematical precocity early in life predicts later creative contributions and leadership in critical occupational roles. On average, males had incomes much greater than their spouses’, whereas females had incomes slightly lower than their spouses’. Salient sex differences that paralleled the differential career outcomes of the male and female participants were found in lifestyle preferences and priorities and in time allocation.

Crimson: ... The gender gap was also apparent in career choice. Men were far more likely to hope to eventually work in finance and entrepreneurship than women, while women were much more likely to aspire to careers in nonprofits and public service, health, and media or publishing. [ Note: these are super high achieving HARVARD kids in the survey, not state-U types ... no one has more "privilege" than they do, so I think it's fair to conclude that they might be expressing their relatively unconstrained actual preferences here. ]

Thursday, November 20, 2014

How well can we predict complex phenotypes in mice from genomic data? The figure below, from a recent Nature Genetics paper (Speed and Balding doi:10.1038/nrg3821), shows prediction accuracies for a set of 139 traits -- including behavioral and disease phenotypes. Significant chunks of heritability are easily captured by linear models with additive effects. The population of mice used in the study are derived from crosses of 8 original inbred strains (see photo). For similar predictive results in dairy cows, see here.

This suggests that human population variation in complex traits is also likely to be approximately linear: mostly due to additive genetic effects. You may have noticed that I am gradually collecting copious evidence for additivity. Far too many scientists and quasi-scientists are infected by the epistasis or epigenetics meme, which is appealing to those who "revel in complexity" and would like to believe that biology is too complex to succumb to equations. ("How can it be? But what about the marvelous incomprehensible beautiful sacred complexity of Nature? But But But ...")

There is a deep evolutionary reason behind additivity: nonlinear mechanisms are fragile and often "break" due to DNA recombination in sexual reproduction. Effects which are only controlled by a single locus are more robustly passed on to offspring. ...

Many people confuse the following statements:

"The brain is complex and nonlinear and many genes interact in its construction and operation."

"Differences in brain performance between two individuals of the same species must be due to nonlinear (non-additive) effects of genes."

The first statement is true, but the second does not appear to be true across a range of species and quantitative traits.

Compare to the additive heritability estimates below. Note the different K's correspond to different choices of genetic similarity matrices (GSMs; see paper). Just ignore all the dots except the ones with largest r2 or h2 for each phenotype. All of the underlying predictive models are linear. It is possible that some phenotypes have even greater broad sense (including non-additive) heritability and that nonlinear models will be required to capture this variation.

Some examples of behavioral traits measured in this mouse population.

EPM: (maze) distance travelled, time spent, and entries into closed and open arms
FN: time taken to sample a novel foodstuff (overnight food deprivation)
Burrowing: Number of pellets removed from burrow in 1.5 hours
Activity: Activity measured in a home cage in 30 minutes
Startle: Startle to a loud noise
Context freezing: Freezing to the context in which a tone is associated with a foot shock
Cue freezing: Freezing to a tone after association with a foot shock

Ursula K. Le Guin, remarks at the National Book Awards. She acknowledged her fellow fantasy and sci-fi writers, who have for so long watched “the beautiful awards,” like the one she received, go to the “so-called realists.”

New Yorker: ... I think hard times are coming, when we will be wanting the voices of writers who can see alternatives to how we live now, and can see through our fear-stricken society and its obsessive technologies, to other ways of being. And even imagine some real grounds for hope. We will need writers who can remember freedom: poets, visionaries—the realists of a larger reality. Right now, I think we need writers who know the difference between production of a market commodity and the practice of an art. The profit motive is often in conflict with the aims of art. We live in capitalism. Its power seems inescapable; so did the divine right of kings. … Power can be resisted and changed by human beings; resistance and change often begin in art, and very often in our art—the art of words. I’ve had a long career and a good one, in good company, and here, at the end of it, I really don’t want to watch American literature get sold down the river. … The name of our beautiful reward is not profit. Its name is freedom.

Tuesday, November 18, 2014

This is the brief filed yesterday against Harvard, alleging discrimination against Asian-American applicants. A related suit was filed against UNC, with perhaps another to come against Wisconsin. Re: the graph above, note that Caltech has race-blind admissions.

... Harvard is engaging in racial balancing. Over an extended period, Harvard’s admission and enrollment figures for each racial category have shown almost no change. Each year, Harvard admits and enrolls essentially the same percentage of African Americans, Hispanics, whites, and Asian Americans even though the application rates and qualifications for each racial group have undergone significant changes over time. This is not the coincidental byproduct of an admissions system that treats each applicant as an individual; indeed, the statistical evidence shows that Harvard modulates its racial admissions preference whenever there is an unanticipated change in the yield rate of a particular racial group in the prior year. Harvard’s remarkably stable admissions and enrollment figures over time are the deliberate result of systemwide intentional racial discrimination designed to achieve a predetermined racial balance of its student body.

The statistical signal of managing fluctuations from year to year (evidence of a race-based target as opposed to independent individual consideration of applicants) might be even stronger for lesser Ivys, which probably see larger variations in yield compared to Harvard. It will be fascinating to see Harvard administrators and admissions officers testifying under oath as to how enrollment by ethnic group has been kept so stable over the years. Legal analysis on SCOTUSblog.

The historical parallels with anti-semitic practices of the early 20th century are reviewed in detail:

... In a letter to the chairman of the committee, President Lowell wrote that “questions of race,” though “delicate and disagreeable,” were not solved by ignoring them. The solution was a new admissions system giving the school wide discretion to limit the admission of Jewish applicants: “To prevent a dangerous increase in the proportion of Jews, I know at present only one way which is at the same time straightforward and effective, and that is a selection by a personal estimate of character on the part of the Admissions authorities ... The only way to make a selection is to limit the numbers, accepting those who appear to be the best.”

... The reduction in Jewish enrollment at Harvard was immediate. The Jewish portion of Harvard’s entering class dropped from over 27 percent in 1925 to 15 percent the following year. For the next 20 years, this percentage (15 percent) remained virtually unchanged.

... The new policy permitted the rejection of scholastically brilliant students considered “undesirable,” and it granted the director of admissions broad latitude to admit those of good background with weaker academic records. The key code word used was “character” — a quality thought to be frequently lacking among Jewish applicants, but present congenitally among affluent Protestants.

This is what our country has come to:

... According to the Princeton Review: "Asian Americans comprise an increasing proportion of college students nationwide. Many Asian Americans have been extraordinarily successful academically, to the point where some colleges now worry that there are ‘too many’ Asian Americans on their campuses. Being an Asian American can now actually be a distinct disadvantage in the admissions processes at some of the most selective schools in the country ...

... If you’re given an option, don’t attach a photograph to your application and don’t answer the optional question about your ethnic background. This is especially important if you don’t have an Asian sounding surname. (By the same token, if you do have an Asian sounding surname but aren’t Asian, do attach a photograph.)"

Please do not comment on this post unless you have read the brief. Comments that are dealt with directly in the brief will be deleted. I hope at least a few serious journalists take the time to read it.

... Schools like Harvard and Princeton brag that each year they reject numerous applicants ... who score a perfect 2400 on the SAT. How would we feel if it were revealed that almost all of these rejected top scorers, year after year, were Asian-Americans? I challenge Harvard and Princeton to refute this possibility.

Addendum: this is one of the plaintiffs, who was rejected by Harvard.

17. Applicant’s parents are first-generation immigrants to the United States from China.

18. Applicant graduated from high school ranked 1 out of 460 students by weighted and un-weighted grade point average.

19. U.S. News and World Report ranks Applicant’s high school in the top 5 percent of all high schools in the United States.

20. Applicant achieved a perfect score of 36 on the ACT. Applicant achieved a perfect score of 800 for SAT II History and a perfect score of 800 for SAT II Math. Among other academic achievements, Applicant was named an AP Scholar with distinction, a National Scholar, and a National Merit Scholarship semifinalist.

21. While in high school, Applicant participated in numerous extracurricular and volunteer activities. Among other things, Applicant was captain of the varsity tennis team, volunteered at a community tennis camp, volunteered for the high school’s student peer tutoring program, was a volunteer fundraiser for National Public Radio, and traveled to China as part of a program organized by the United States Consulate General and Chinese American Students Education and Exchange to assist students in learning English writing and presentation skills.

Thursday, November 13, 2014

These results suggest that autism spectrum disorder (ASD) in high functioning males may be a different condition than ASD in low-IQ males and females. They also suggest many gene targets in which small "nicks" could result in lower IQ. I believe that at least part of "normal" population variation in IQ is due to effects like these.

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

The revolution in genetic engineering that will make it possible for humans to actively manage our evolutionary process for the first time in our species’ history is already under way. In laboratories and clinics around the world, gene therapies are being successfully deployed to treat a range of diseases, including certain types of immune deficiency, retinal amaurosis, leukemia, myeloma, hemophilia, and Parkinson’s. This miraculous progress is only the beginning. The same already existing technologies that will soon eliminate many diseases that have victimized humans for thousands of years will almost certainly be used eventually to make our species smarter, stronger, and more robust.

The prospect of genetic engineering will be exciting to some, frightening to others, and challenging for all. If not adequately addressed, it will also likely lead to major conflict both within societies and globally. But although the science of human genetic engineering is charging forward at an exponential rate, the global policy framework for ensuring this scientific progress does not lead to destabilizing conflict barely exists at all. The time has come for a meaningful dialogue on the national security implications of the human genetic revolution that can lay the conceptual foundation for a future global policy structure seeking to prevent dangerous future conflict and abuse. ...

... Crick, 35, had already had a career in physics interrupted by the war and despaired of making his great contribution to science. Watson was a callow 23, fresh from Indiana.

It was clear to me that I was faced with a novelty: enormous ambition and aggressiveness, ... I am sure that, had I had more contact with, for instance, theoretical physicists, my astonishment would have been less great. In any event, there they were, speculating, pondering, angling for information. ...

Thanks for digging around down there -- what did you find, again? Great! I've got more horsepower, so I'll just connect the dots for you now... :-) From Wikipedia on Crick:

Crick had to adjust from the "elegance and deep simplicity" of physics to the "elaborate chemical mechanisms that natural selection had evolved over billions of years." He described this transition as, "almost as if one had to be born again." According to Crick, the experience of learning physics had taught him something important—hubris—and the conviction that since physics was already a success, great advances should also be possible in other sciences such as biology. Crick felt that this attitude encouraged him to be more daring than typical biologists who tended to concern themselves with the daunting problems of biology and not the past successes of physics.

Friday, November 07, 2014

This morning I attended an excellent talk: Adaptive Evolution of Gene Expression (see paper and video below), by Hunter Fraser of Stanford.

His results support the hypothesis that non-coding regions of the genome play at least as large a role in evolution and heritable variation as protein coding genes.

From an information-theoretic perspective, it seems obvious that there is much more information in the whole genome than in the ~20k coding regions. Without the additional information, it would not be possible to produce diverse organisms such as flies, worms, fish, and humans from very similar sets of genes/proteins. Strangely, though, I've found most biologists to be overly focused on protein sequences. Perhaps results like these will finally modify this prior.

The molecular basis of adaptation—and in particular the relative roles of protein-coding vs. gene expression changes—has long been the subject of speculation and debate. Recently, the genotyping of diverse human populations has led to the identification of many putative “local adaptations” that differ between populations. Here I show that these local adaptations are over 10-fold more likely to affect gene expression than amino acid sequence. In addition, a novel framework for identifying polygenic local adaptations detects recent positive selection on the expression levels of genes involved in UV radiation response, immune cell proliferation, and diabetes-related pathways. These results provide the first examples of polygenic gene expression adaptation in humans, as well as the first genome-scale support for the hypothesis that changes in gene expression have driven human adaptation.

This is video of a similar talk at Berkeley.

Note Added: As I mentioned above, simple considerations suggest that the machinery of life must be much more complex than the diversity of specific proteins.

(This article is based on the Allan Wilson Memorial Lectures given at the University of California at Berkeley in October 2004.)

In their classic paper “Evolution at Two Levels in Humans and Chimpanzees,” published exactly 30 years ago, Mary-Claire King and Allan Wilson described the great similarity between many proteins of chimpanzees and humans [1]. They concluded that the small degree of molecular divergence observed could not account for the anatomical or behavioral differences between chimps and humans. Rather, they proposed that evolutionary changes in anatomy and way of life are more often based on changes in the mechanisms controlling the expression of genes than on sequence changes in proteins.

This article was a milestone in three respects. First, because it was the first comparison of a large set of proteins between closely related species, it may be considered one of the first contributions to “comparative genomics” (although no such discipline existed for another two decades). Second, because it extrapolated from molecular data to make inferences about the evolution of form, it may also be considered a pioneering study in evolutionary developmental biology. And third, its focus on the question of human evolution and human capabilities, relative to our closest living relative, marked the beginning of the quest to understand the genetic basis of the origins of human traits. Like much of Wilson and his colleagues' body of work, this contribution had a great influence on paleoanthropologists as well as molecular biologists.

The 30th anniversary of this landmark article arrives at a moment when comparative genomics, evolutionary developmental biology, and evolutionary genetics are pouring forth unprecedented amounts of new data, and the entire chimpanzee genome is available for study. It is therefore an opportune time to examine what has been and is being revealed about the relationship between evolution at the two levels of molecules and organisms, and to assess the status of King and Wilson's hypothesis concerning the predominant role of regulatory mutations in organismal evolution.

King and Wilson used the phrase “ways of life” to include both physiology and behavior (M.-C. King, personal communication) and proposed that the evolution of both anatomy and ways of life was governed by regulatory changes in the expression of genes. From the outset of this review, I make the sharp distinction between the evolution of anatomy and the evolution of physiology. Changing the size, shape, number, or color patterns of physical traits is fundamentally different from changing the chemistry of physiological processes. There is ample evidence from studies of the evolution of proteins directly involved in animal vision [2], respiration [3], digestive metabolism [4], and host defense [5] that the evolution of coding sequences plays a key role in some (but not all) important physiological differences between species. In contrast, the relative contribution of coding or regulatory sequence evolution to the evolution of anatomy stands as the more open question, and will be my primary focus.

The amount of direct evidence currently in hand is modest, and includes examples of both the evolution of coding and of non-coding, regulatory sequences contributing to morphological evolution. However, I will develop the argument, on the basis of theoretical considerations and a rapidly expanding body of empirical studies, that regulatory sequence evolution must be the major contributor to the evolution of form.

This conclusion poses particular challenges to comparative genomics. While we are often able to infer coding sequence function from primary sequences, we are generally unable to decipher functional properties from mere inspection of non-coding sequences. This has led to a bias in comparative genomics and evolutionary genetics toward the analysis and reporting of readily detectable events in coding regions, such as gene duplications and protein sequence evolution, while non-coding, regulatory sequences are often ignored. However, approximately two-thirds of all sequences under purifying selection in our genome are non-coding [6]. One consequence of the underconsideration of non-coding, regulatory sequences is unrealistic expectations about what can currently be learned about the genetic bases of morphological diversity from comparisons of genome sequences alone. The visible diversity of any group is not reflected by the most visible components of gene diversity—that is, the diversity of gene number or of coding sequences. In order to understand the evolution of anatomy, we have to study and understand regulatory sequences, as well as the proteins that connect them into the regulatory circuits that govern development. I will begin with some historical and theoretical considerations about regulatory and coding sequence evolution, then delve into the insights offered by specific experimental models of anatomical evolution, and finally, I will revisit King and Wilson's original focus and discuss how our emerging knowledge of the evolution of form bears on current efforts to understand human evolution. ...

... Thus, while the coding sequences of the structural and regulatory proteins are constrained by pleiotropy, modular cis-regulatory regions enable a great diversity of patterns to arise from alterations in regulatory circuits through the evolution of novel combinations of sites for regulatory proteins in cis-regulatory elements [35]. This diversity is produced by the sort of “tinkering” with existing components envisaged by Jacob [19]. ... The available evidence suggests ... that the diversification of other traits that are governed by highly pleiotropic and well-conserved proteins can also be accounted for by regulatory sequence evolution.

... Based upon (i) empirical studies of the evolution of traits and of gene regulation in development, (ii) the rate of gene duplication and the specific histories of important developmental gene families, (iii) the fact that regulatory proteins are the most slowly evolving of all classes of proteins, and (iv) theoretical considerations concerning the pleiotropy of mutations, I argue that there is adequate basis to conclude that the evolution of anatomy occurs primarily through changes in regulatory sequences. ...

Tuesday, November 04, 2014

Looks like an interesting new magazine: JSTOR Daily provides insight, commentary, and analysis of ideas, research, and current events, tapping into the rich library of scholarship on JSTOR. (For non-academics, JSTOR is an online journal repository.)

The out-of-control hookup culture on American college campuses has become a predictable subject for magazine articles, op-ed pages and blogs over the past decade or more. It’s terrific in that role, mixing titillation with a narrative of moral decline among elite young people, and giving commentators a chance to tisk at kids these days. ...

What’s Really Changing?

A recent paper by Martin Monto and Anna Carey of the University of Portland confirmed what scholars looking at sexual behavior on campus have known for a while—the notion of modern campuses as a non-stop sex-fueled party is massively overblown. Looking at survey data from two groups of students, one that was in school from 1988 to 1996 and the other from 2004 to 2012, Monto and Carey found that the “hookup era” kids didn’t have more sex, or more partners, than the earlier group. However, there was a fairly small drop in the percentage with a regular sexual partner, with more respondents saying they’d had sex with a friend or a “casual date or pickup” instead.

Writing in the American Sociological Association magazine Contexts, Elizabeth A. Armstrong of the University of Michigan, Laura Hamilton of the University of California, Merced, and Paula England of New York University agree that modern campus culture isn’t a big departure from the recent past. The big change came with the Baby Boom’s sexual revolution, and increases in casual sex since then have been relatively gradual. ...

Kind of disappointing that Tinder and Facebook and other social networking tools didn't lead to more action on campus.

When I finished my PhD at Berkeley I relocated to Cambridge, MA. I found an aging hippie (turned lawyer) through the "ride board" at the student center to share part of the drive. The stories he told during our cross country trip left me with no doubt that my generation, which came of age during the AIDS epidemic, had a pretty dull time compared to his cohort, which enjoyed free love and other goodies. A few years later I met some chicas de Sevilla who informed me that their sexual revolution had only happened recently, post-Franco :-)

Monday, November 03, 2014

Discussion of the Chinese role in the recent bubble (also, use of ASICs for mining) starting @15min or so. E-payment situation (Alipay, WeChat, etc.) in PRC described @24min.

Sinica podcast: ... Joined by Zennon Kapron, fintech expert, owner of the Shanghai consultancy Kapronasia, and recent author of the book Chomping at the Bitcoin, we delve into the driving forces behind the cryptocurrency revolution in China, as well as take a quick look at the various other kinds of innovation surfacing in China's online financial sector.